Is CTSF p.Pro426Ser (c.1276C>T) pathogenic?

CTSF p.Pro426Ser (c.1276C>T) is classified Uncertain significance in CTSF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.1623); Very rare (popmax 8.53e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTSF p.Pro426Ser (c.1276C>T)?

CTSF p.Pro426Ser (c.1276C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CTSF p.Pro426Ser (c.1276C>T) in the general population?

CTSF p.Pro426Ser (c.1276C>T) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about CTSF p.Pro426Ser (c.1276C>T)?

AlphaMissense predicts likely benign (score 0.1623) — an in-silico prediction, not a clinical call.

CTSF p.Pro426Ser

c.1276C>T · VCV4008168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1623	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.53e-05% European (non-Finnish) · 1/1,172,612 alleles

Overall 6.92e-05% 1/1,445,216 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CTSF
Protein: p.Pro426Ser
Coding: c.1276C>T
MANE Select: NM_003793
Type: single nucleotide variant
Location: chr11:66564603 (GRCh38)
Gene constraint: LOEUF 1.296 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.78 · 1 PDB
Residue 426: a disulfide bond

Full CTSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTSF c.1045+1G>T Likely pathogenic ★★ same condition
CTSF p.Arg217Ter Pathogenic ★★ same condition
CTSF p.Arg121Pro Uncertain significance ★★ ⚠ same condition
CTSF p.Arg196Trp Uncertain significance ★★ ⚠ same condition
CTSF p.Arg418Cys Uncertain significance ★★ ⚠ same condition
CTSF p.Arg421Gln Uncertain significance ★★ ⚠ same condition
CTSF p.Arg54Gly Uncertain significance ★★ ⚠ same condition
CTSF p.Asn213Lys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ctsf-p-pro426ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown